Erythropoietin (EPO) is a glycoprotein produced in the kidney, and is the principal hormone responsible for stimulating red blood cell production (erythrogenesis). EPO stimulates the division and differentiation of committed erythroid progenitors in the bone marrow. Normal plasma erythropoietin levels range from 0.01 to 0.03 Units/mL, and can increase up to 100 to 1,000-fold during hypoxia or anemia. Graber and Krantz, Ann. Rev. Med. 29:51 (1978); Eschbach and Adamson, Kidney Intl. 28:1 (1985). Recombinant human erythropoietin (rHuEpo or epoetin alfa) is commercially available as EPOGEN.RTM. (epoetin alfa, recombinant human erythropoietin) (Amgen Inc., Thousand Oaks, Calif.) and as PROCRIT.RTM. (epoetin alfa, recombinant human erythropoietin) (Ortho Biotech Inc., Raritan, N.J.). EPO is indicated for treatment of anemia, including anemias associated with cancer chemotherapy, chronic renal failure, malignancies, adult and juvenile rheumatoid arthritis, disorders of haemoglobin synthesis, prematurity, and zidovudine treatment of HIV infection.
The vascular endothelium is a layer of cells lining the inner vascular wall and in direct contact with blood, providing an active natural barrier between the circulatory and extravascular compartment. The endothelium is involved in signal and information transfer at the cellular, tissue and organ level, and plays a role in both cell-mediated and humoral immune responses. Endothelial cells are metabolically active and normally produce a number of substances with effects on the vascular lumen and on platelets. Endothelial vasodilators include prostacyclin (PGI.sub.2) and endothelium-derived relaxing factor (EDRF, which may be nitric oxide or a more stable adduct thereof); these two substances also act to inhibit platelet aggregation.
Damage or destruction of the endothelium by physical trauma or disease processes such as atherosclerotic plaque formation may impair EDRF production, contributing to vasoconstriction. More diffuse and subtle endothelial damage, such as due to chronic hypertension or reperfusion after ischemia, also leads to altered EDRF production. Endothelial products localized to the luminal endothelial surface include ectoADPase and thrombomodulin. Vasoconstrictors released by the endothelium include endothelin. Endothelial cells also secrete growth factors which enhance endothelial mitogenesis and can induce new blood vessel formation (angiogenesis). It has been reported that granulocyte macrophage-colony stimulating factor (GM-CSF) and granulocyte-colony stimulating factor (G-CSF) stimulate proliferation and migration of endothelial cells. Interleukin-3 (IL-3) also enhances the proliferation of these cells. See Bussolino et al., Nature 337:471 (1989); Brizzi et al., J. Clin. Invest. 91:2887 (1993).